Over 40 epidemiological studies and one clinical trial have found a protective effect of male circumcision (MC) against HIV acquisition in men. A meta-analysis of African studies has demonstrated an adjusted reduction in HIV risk of 45% in the general population and 70% among high risk groups. A clinical trial in South Africa demonstrated a 60% protective effect, with a 76% effect in a per-protocol analysis. In addition, uncircumcised men are at higher risk for acquisition of certain sexually transmitted infections (STIs), which in turn increase HIV susceptibility. These data have led to calls for male circumcision to be considered as an HIV prevention strategy, especially in areas of high HIV prevalence. However, at meetings held by UNAIDS, the World Health Organization, UNICEF and others, researchers and policy makers have concluded that clear evidence of a protective effect from additional randomized controlled trials (RCTs) is required before MC can be advocated for HIV prevention. This application seeks support for continuation of a randomized controlled trial of male circumcision in Kisumu, Kenya. The main objective is to assess the effectiveness of MC in reducing HIV incidence in young, sexually active men. Uncircumcised HIV seronegative men aged 18-24 years are randomized into either the treatment (circumcision) or control arm and followed for two years, with regular behavioral and STI assessments, as well as HIV testing and counseling. The primary endpoint is HIV incidence, with surgical complications, STI incidence, and behavioral risk as secondary outcomes. Enrollment of 2784 young men was completed September 2005. This sample size will provide 80% power to detect a 50% reduction in HIV incidence over two years. So far, just 11% of person-years have been missed due to participants not reporting for study visits; rates of HIV and STI incidence are consistent with original projections. Thus the study is on track to meet the original objectives and to provide a clear answer to the question of whether male circumcision reduces HIV incidence. Because any effect of MC could be diluted after 24 months through differential changes in behavior by circumcised versus uncircumcised men, we propose to extend follow-up beyond two years on a sub-cohort of participants. Since MC is little practiced in the high HIV prevalence regions of Africa, the results of this trial could have a very significant impact on the HIV/AIDS pandemic. [unreadable] [unreadable] [unreadable] [unreadable]